Alzheimer's disease (AD) remains a major health problem in the U.S., and as life expectancy continues to increase, the number of AD patients presenting for surgery and anesthesia will rise. The etiology of AD is probably multifactorial; however, recent studies suggest that general anesthetics may contribute to the development and exacerbation of this neurodegenerative disorder. Intraneuronal neurofibrillary tangles, composed of aggregated hyperphosphorylated tau protein, are one of the main neuropathological hallmarks of AD, and anesthetics have been previously demonstrated to accelerate tau pathology in vivo, albeit indirectly, by inducing profound hypothermia. However, exciting and novel preliminary data generated for this proposal demonstrate that certain anesthetics (propofol and dexmedetomidine), which are often clinically administered for prolonged periods of time, can themselves directly hyperphosphorylate tau dose-dependently under normothermic conditions, both in vivo and in vitro. Hence, we hypothesize that the prolonged administration of anesthesia, under normothermic conditions, results in dose-dependent increases in hippocampal and cortical tau phosphorylation, neurofibrillary pathology as well as neurocognitive impairment and that these changes are amplified in the presence of pre-existing tau pathology. The following specific aims will test these hypotheses: Aim 1: To confirm that prolonged normothermic anesthesia exposure leads to dose-dependent increases in tau phosphorylation and aggregation in vivo and in vitro. Aim 2: To understand the mechanism underlying tau phosphorylation and aggregation following prolonged normothermic anesthesia exposure in vivo. Aim 3: To investigate the functional and behavioral effects of tau-related changes following prolonged normothermic anesthesia exposure in vivo. Relevance: These studies are unique in that they will use nontransgenic mice and AD transgenic mice expressing human tau (hTau) to establish the impact of prolonged normothermic exposure to clinically relevant anesthetics on tau phosphorylation, aggregation, pathology as well as function and will establish the impact of these changes in tau on memory. Also, a neuroblastoma cell line, stably transfected to overexpress human tau, will be used to determine for the first time, the direct impact of these anesthetics on tau phosphorylation in vitro. Moreover, immunoblot analyses and tau kinase/phosphatase assays will be utilized to determine the mechanisms by which prolonged normothermic anesthesia exposure induces tau hyperphosphorylation in vivo. This information is critical for attaining the long-term goal of preventing an acceleration of tau pathology and cognitive impairment in the growing number of patients, with or at risk for AD, who require anesthesia.